Systemic lupus erythematosus (SLE) affects ~ 2 million Americans with devastating impact on multiple organs, especially the skin, joints, kidney, and brain. Therapeutic strategies for lupus are largely palliative or immunosuppressive with serious toxicities. No new drugs for SLE have been approved in decades. Thus, novel therapeutic approaches to lupus - particularly therapeutics that treat the underlying causes of the disease - are in great demand. Our goals are to translate insights in the molecular mechanisms underlying SLE into the therapeutic arena. With phase 1 support we will sufficiently characterize a novel set of candidate small molecule lupus therapeutics to warrant the investment of further resources for drug development. SLE is characterized by the production of autoantibodies, many of which have specificity for nuclear antigens, in particular, DNA. These anti-DNA antibodies are now known to cross-react avidly with non-DNA (e.g., protein) antigens and this cross-reactivity contributes to lupus pathogenesis. Dr. Diamond, Head, Center for Autoimmune and Musculoskeletal Diseases (Feinstein) has performed pioneering studies on the induction and pathogenicity of anti-DNA antibodies in both clinical lupus and in various mouse animal models and identified a specific pentapeptide (DWEYS) that is present in the N methyl D aspartate receptor (NMDAR) as a cross- reactive protein antigen for the anti-dsDNA autoantibodies that are common in lupus patients. Exogenously supplied DWEYS peptide blocks the pathogenic deposition of anti-DNA antibodies in critical target tissues. Our hypothesis is that lupus peptidomimetics that preferentially bind to and neutralize this subset of anti-DNA autoantibodies will be effective therapeutics in patients. Since exogenous peptides like DWEYS have short half-lives in vivo, the Feinstein initiated a structural peptidomimetic program to create non-peptide organic compounds that will work analogously, but with preferred characteristics, to the DWEYS peptide. Feinstein and Biomedical Research Models, Inc (BRM), a small business with expertise in drug development testing and a particular emphasis in autoimmune models, now propose a joint venture to begin assessing the drug-like properties of these small molecule therapeutics. BRM will establish whether Feinstein's candidate lupus peptidomimetic small molecules possess valid drug-like properties to support preparation of a pre- investigational new drug (pre-IND) package. The Specific Aims are: 1. Synthesize new peptide/DNA mimetope small molecules and determine their rank order of efficacy in in vitro assays. 2. Characterize the lead and back-up lead in terms of tissue distribution, pharmacokinetics, immunogenicity, as well as residual host immunocompetence, using acute and chronic treatment. 3. Initiate preclinical evaluation of small molecule peptidomimetics in spontaneous and genetic murine models of lupus: NZB/W, MRL/lpr. The net result of this effort will be to develop a novel treatment for SLE and improve the lives of Americans. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE) affects multiple organs, especially the skin, joints, kidney, and brain in ~ 2 million Americans. Current SLE therapeutics treat disease symptoms and have serious side-effects. Herein, we describe a novel therapeutic approach to lupus that will treat the underlying cause of the disease, rather than its many symptoms and will result in a novel therapy for Americans.